Letter Cite This: Org. Lett. 2018, 20, 1789−1793
pubs.acs.org/OrgLett
Ligand-Controlled Rhodium-Catalyzed Site-Selective Asymmetric Addition of Arylboronic Acids to α,β-Unsaturated Cyclic N‑Sulfonyl Ketimines Chun-Yan Wu,†,‡ Yu-Fang Zhang,†,‡ and Ming-Hua Xu*,† †
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China ‡ University of Chinese Academy of Sciences, Beijing 100049, China S Supporting Information *
ABSTRACT: A site-selective rhodium-catalyzed asymmetric 1,4-/1,2-addition of arylboronic acids to challenging α,βunsaturated cyclic ketimines was realized through a ligand-controlled strategy. By employing different chiral olefin ligands, a ligand-controlled switch in the reaction regioselectivity was attained for the first time. The reactions allow the synthesis of highly valuable α,α-disubstituted chiral allylic amines and enantioenriched 1,4-adducts. Further product transformation provided easy access to various quaternary carbon-containing chiral amines and amino acid derivatives bearing multifunctional groups.
R
rhodium-catalyzed sequential 1,4-/1,2-addition reactions with arylboronic acids by employing different chiral olefin ligands, which allowed the rapid construction of benzosulfamidates bearing two gem-diaryl stereocenters with high enantiopurities (Scheme 1a).4j Despite the notable success in achieving regio-
hodium-catalyzed asymmetric addition of organoboron reagents to electron-deficient olefins,1,2 imines,3,4 and carbonyl compounds5 constitutes an important and powerful method for the construction of carbon−carbon bonds. Among the electron-deficient conjugated substrates, α,β-unsaturated imines represent an intriguing class of substrates, as they might be subjected to 1,4-addition and 1,2-addition simultaneously under rhodium catalysis. Surprisingly, despite the fact that many beautiful examples of asymmetric 1,2-addition of imines have been realized,3,4 to our knowledge, the utilization of α,βunsaturated imines for stereoselective 1,2-addition to access chiral allylic amines has not been reported. On the other hand, asymmetric 1,4-addition of α,β-unsaturated imines is also rarely explored, in sharp contrast to the achievements with α,βunsaturated ketones/esters/amides.1,2 Only recently has a successful example of rhodium-catalyzed enantioselective 1,4addition of arylboronic acids to α,β-unsaturated imino esters using a chiral bicyclic bridgehead phosphoramidite ligand been disclosed, which allowed the synthesis of γ,γ-diaryl-α,βdehydroamino esters.6 Therefore, achieving either 1,4- or 1,2addition of α,β-unsaturated imines in a regio- and enantioselective manner remains a particularly challenging task. It would be ideal to develop a regiodivergent highly enantioselective addition of α,β-unsaturated imines through ligand/catalyst tuning. Over the past few years, our group has been interested in rhodium-catalyzed enantioselective addition of imines using simple chiral olefins as ligands.3c,f,g,4c,g−k,7 With challenging α,βunsaturated cyclic N-sulfonyl ketimines, we recently developed a catalytic stereoselective double arylation process through © 2018 American Chemical Society
Scheme 1. Rh-Catalyzed Asymmetric 1,4-/1,2-Addition of α,β-Unsaturated Ketimines
and enantioselective 1,4-addition of these α,β-unsaturated ketimines, it is exceedingly difficult to access α,α-disubstituted chiral allylic amines via direct 1,2-addition by tuning the catalyst system. The low reactivity of the CN may be attributed to the double conjugation with the CC and aromatic ring in the molecule. To address this issue, we designed an unprecedented type of α,β-unsaturated cyclic ketimines8 and wanted to achieve Received: January 27, 2018 Published: March 13, 2018 1789
DOI: 10.1021/acs.orglett.8b00289 Org. Lett. 2018, 20, 1789−1793
Letter
Organic Letters Table 1. Optimization of Reaction Conditionsa
both asymmetric 1,4- and 1,2-addition through direct control of the chiral ligand. Herein, we describe the first example of rhodium-catalyzed site-selective asymmetric addition of arylboronic acids to α,β-unsaturated cyclic ketimines (Scheme 1b). A ligand-controlled switch in the reaction regioselectivity was attained. Our initial investigation was carried out by evaluating the reaction of the newly designed α,β-unsaturated five-membered cyclic N-sulfonyl imine 1a with p-methoxyphenylboronic acid 2a under conditions similar to our previously reported ones in the presence of the optimal C1-symmetric chiral diene ligand9 and branched sulfur-olefin ligand (Scheme 2). The diene ligand
3a
Scheme 2. Ligand Screening
L1 exhibited truly excellent catalytic reactivity for 1,4-addition, giving the corresponding β-gem-diaryl substituted ketimine 3a solely with commendable enantioselectivity (86% ee). For comparison, C2-symmetric diene ligand L3 was evaluated; however, a much lower ee was obtained. Gratifyingly, by examination of the substituents on the phenyl ring of chiral [2.2.2]dienes, ligand L5 bearing a pentafluorobenzene moiety was found to be superior to the others, giving the sole 1,4addition product in 92% yield and 93% ee. On the other hand, we were very pleased to find that the sulfur-olefin ligand L6 showed exclusive 1,2-addition performance, which led to the formation of the desired quaternary-containing 1,2-adduct 4a with extremely high ee (99%), albeit in low yield (10%). Inspired by these promising results, further examination on the reaction parameters including additive, solvent, temperature, catalyst loading, and reactant ratio were subsequently carried out (Table 1). As for 1,4-addition, among the various additives (entries 1−5), the enantioselectivity remained nearly constant and KOH gave the best yield (94%) (entries 1−5). Varying the solvent did not furnish better results (entries 6−7). Lowering the catalyst loading would lead to a somewhat diminished yield, while still maintaining the enantioselectivity (entry 8). Notably, no 1,2-adducts formation was observed even with an excess amount of arylboronic acid 2a. In the study of 1,2-addition, we investigated the effect of temperature (entries 10−14). An increase to 41% was observed at 80 °C (entry 11); however, no further improvement was attained at higher temperature (entry 12). The screening of additives indicated that KF could facilitate rhodium/sulfur-olefin L6 in exhibiting better catalytic activity, giving the 1,2-adduct 4a in 49% yield with 98% ee (entry 16). In the presence of 1.0 equiv of aqueous KF (1.5 M), the reaction afforded 4a in a slightly increased yield (54%, entry 17). Fortunately, increasing the amount of p-methoxyphenylboronic acid was found to be beneficial to the 1,2-addition yield. With 6 equiv of arylboronic acid, the reaction proceeded with high efficiency and great
entry
L
additive
t (°C)
yield (%)b,c
1 2 3 4 5 6d 7e 8f 9 10 11 12 13 14 15 16 17g 18g,h 19g,i
L5 L5 L5 L5 L5 L5 L5 L5 L6 L6 L6 L6 L6 L6 L6 L6 L6 L6 L6
K2HPO4 KOH K3PO4 KF KHF2 KOH KOH KOH K2HPO4 K2HPO4 K2HPO4 K2HPO4 KHF2 K3PO4 KOH KF KF KF KF
rt rt rt rt rt rt rt rt rt 50 80 100 80 80 80 80 80 80 80
92 94 90 76 88 15 79 85
